What can belimumab and anifrolumab do?

The monoclonal antibodies belimumab and anifrolumab are both approved for the treatment of systemic lupus erythematosus (SLE). Their response is considered to be highly effective. The point at which they should be used in therapy was discussed on the basis of two case studies at the congress of the German Society for Internal Medicine (DGIM).

In January 2019, a 52-year-old female patient with secondary antiphospholipid syndrome and systemic lupus erythematosus (SLE) presented to Dr. Johanna Mucke, Department of Rheumatology, University Hospital Düsseldorf, Germany, for evaluation of recurrent angioedema with high steroid requirements and optimization of lupus therapy. The initial diagnosis of SLE was made in Maastricht in 2012. At that time, high-titer ANA 1:1280 was detected, and detection of dsDNA and SSA-AK was positive in each case. The woman suffered from arthritis, fatigue and lassitude, complained of cognitive impairment, serositis, and had DVT on the right, pulmonary embolism, and sinus vein thrombosis. In this context, antiphospholipid antibodies have also been detected (triple positive). The Dutch physicians diagnosed SLE with secondary APS.

The patient received therapy with hydroxychloroquine (HCQ) and prednisolone plus oral anticoagulation with marcoumar and vitamin D. Under HCQ, she developed exanthema with suspected toxic epidermal necrolysis. In the further course, she first received azathioprine, under which she developed leukopenia, then methotrexate with the consequence of aphthosis, so that she finally decided not to continue therapy and permanently took only 10-15 mg prednisolone.

This worked well until she developed four recurrent angioedema episodes during 2018. Hereditary angioedema was excluded. The problems got to the point where she had an upper airway obstruction and had to be resuscitated. Since then, she had a tracheostomy because she was worried about a recurrence. In November 2018, she presented again to her rheumatologist: According to her physician’s letter, she complained of loss of appetite, had high analgesic and cortisone requirements, persistent pain in her fingertips and toes, fatigue, morning stiffness, and nonspecific pain (VAS 8/10). Due to inadequate disease control, the recommendation was to present to a clinic.

Woman felt well – under 37.5 mg prednisolone

When the woman subsequently saw Dr. Mucke, she reported a satisfactory condition with no relevant adverse effects – taking Marcumar, vitamin D, and prednisolone monotherapy at 37.5 mg. “No wonder she was doing very well,” noted the rheumatologist [1]. Physical examination revealed no abnormalities; she had only the inserted tracheostoma and no neurologic deficit. Laboratory chemistry showed normal renal values, high titer ANA (>1:2560), SSA could be detected and ELISA also showed dsDNA-AK (4425 IU/ml).

A previously performed cMRI showed nonspecific gliosis foci and caliber variations. “Since the patient had no neurological abnormalities, we initially interpreted this as controlled disease activity under a lot of cortisone.” The Düsseldorf specialists decided to reduce steroids and initiate therapy with belimumab.

Belimumab is a BLyS antibody that inhibits B-cell activation. Extrarenally, it has already been approved in Switzerland since 2012 for active, autoantibody-positive SLE with high disease activity despite standard therapy (e.g., detection of anti-dsDNA-AK and low complement). Approval for lupus nephritis as add-on therapy in combination with MMF, CYC or AZA for maintenance followed in Germany in 2021 and in Switzerland in 2022. Belimumab significantly reduces disease activity in the long term and was also able to improve quality of life and fatigue in Patient Reported Outcomes. Pooled analysis showed that the agent is particularly effective in patients with high disease activity and high serologic activity who have high cortisone or steroid requirements.

In February 2023, the patient presented again to Dr. Mucke in good general condition. She no longer had angioedema and fatigue had improved. She complained of recurrent “brain fog,” but this had also improved since the start of treatment; a repeat cMRI showed no new changes. Intermittent arthralgias occur, but no joint swelling. The cortisone could be reduced slowly but steadily, currently the woman is still taking 3.5 mg. She has no disease activity and is thus in remission.

Anifrolumab shows rapid response

Also 52 years old was a patient reported by Prof. Dr. Andreas Schwarting, head of the focus on rheumatology and clinical immunology at the University Medical Center Mainz and medical director at the Rheumatism Center Rhineland-Palatinate. The woman had discoid LE (first diagnosed in 1992), stomatitis, arthritis, Raynaud’s syndrome, and cardiac involvement (perimyocarditis). Laboratory showed ANA, anti-dsDNA and anti-SSA positive, she suffered from anemia and leukocytopenia, C3, C4 were normal. As secondary diagnoses, the patient had a severe leg vein thrombosis from 1997 and osteoporosis (rib and LWK fractures), which led Prof. Schwarting to suspect that too much cortisone may have been administered. There was a recurrent H. zoster disease, Z.n. CMV reactivation and the woman had migraine.

In initial therapy, the woman received hydroxychloroquine (HCQ) according to EULAR recommendations until she developed allergy in 2014, plus low-dose glucocorticoids until 2013. Azathioprine mono proved ineffective; further, CMV reactivation occurred with cyclosporine. Since 2007, the patient had been taking mycophenolate mofetil (MMF), plus Marcumar, NSAIDs, and vitamin D. From 2011 to 2016, she received belimumab, but not with the desired success.

In 2016, Prof. Schwarting and his team arranged for the woman to be enrolled in the TULIP pivotal anifrolumab trial with high clinical activity at that time. She quickly showed a good response, so MMF was initially reduced to 500 mg/d. After one and a half years, she was enrolled in a long extension study (LTE). In 2018, she entered complete clinical remission (cSLEDAI 0), after which MMF was completely discontinued; she was no longer taking glucocorticoids by that time. The LTE ended in October 2020: “So we had no more therapy for the patient,” the rheumatologist explained. At presentations in December 2020 and February 2021, the woman was still stable without medication, but from March 2021, arthralgias, skin changes, and fatigue set in. “From then on, it became difficult, but after three months, there was an opportunity to use anifrolumab in a compassionate use program (CUP) before it was approved. It then took another seven months, but she was back in complete remission in December 2021.”

Skin involvement shows particularly good response

The pivotal studies included mainly Caucasians with high to highly active lupus, Prof. Schwarting explained. Such patients, who are also under glucocorticoids, HCQ and immunosuppression, and whose interferon gene signature is high, seem particularly suitable for the agent, according to the expert. “Skin involvement shows a particularly good response with anifrolumab.” Anti-dsDNA does not appear to be an influencing factor on response based on the study data, but low C3, C4 does. Whether patients were pretreated with biologics or naïve did not matter for response, nor did side effects occur more frequently. “Treatment-refractory cases on basic therapy responded well to the new agent,” Prof. Schwarting said.

The expert described the effect of Afrinolumab in this patient as “enormously effective”. However, he cautioned that there is currently no approval for lupus nephritis and long-term data are also lacking. “We now regard belimumab almost as a kind of basic drug, but intensive skin involvement, treatment refractoryity and the rapid response argue in favor of anifrolumab.” Although the agent is not approved as a monotherapy, individual cases like the one described show that for some patients on anifrolumab, there is no longer any need to continue cortisone or an immunosuppressant at all, he concluded.

Congress: DGIM 2023

Sources:

1. Sitzung «Was können die neuen Lupus-Medikamente?»; Vortrag: «Fall 1 – Belimumab»; 129. Kongress der DGIM, 22.04.2023.
2. Sitzung «Was können die neuen Lupus-Medikamente?»; Vortrag: «Fall 2 – Anifrolumab»; 129. Kongress der DGIM, 22.04.2023.

InFo RHEUMATOLOGIE 2023; 5(1): 18–20